The present invention relates generally to peritoneal dialysis. More specifically, the present invention relates to improved peritoneal dialysis solutions including polypeptides.
It is known to use dialysis to support a patient whose renal function has decreased to the point where the kidneys no longer sufficiently function. Two principal dialysis methods are utilized: hemodialysis; and peritoneal dialysis.
In hemodialysis, the patient""s blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal treatment that requires special machinery, there are certain inherent disadvantages with hemodialysis.
To overcome the disadvantages associated with hemodialysis, peritoneal dialysis was developed. Peritoneal dialysis utilizes the patient""s own peritoneum as a semipermeable membrane. The peritoneum is a membranous lining of the; body cavity that due to the large number. of blood vessels and capillaries is capable of acting as a natural semipermeable membrane.
In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. This allows the proper acid-base, electrolyte and fluid balance to be returned to the blood. and the dialysis solution is simply drained from the body cavity through the catheter.
Although there are many advantages to peritoneal dialysis, one of the difficulties that has been encountered is providing a dialysate that includes a suitable osmotic agent. What is required is that a sufficient osmotic gradient is achieved. The osmotic agent is used in the dialysis solution to maintain the osmotic gradient required to cause transport of water and toxic substances across the peritoneum into the dialysis solution.
The appropriate osmotic agent needs to achieve at least a couple criteria. First, it needs to be non-toxic and substantially biologically inert. However, the agent should be metabolizable. Additionally, the agent should not rapidly cross the peritoneal membrane into the blood. By achieving both these criteria, this would allow maintenance of the maximum ultrafiltration gradient, and also would prevent toxicity or accumulation of unwanted substances in the blood.
No currently used substance completely satisfies the criteria for an osmotic agent in a dialysis solution. Presently, the osmotic agent that is most widely used is dextrose. Dextrose is fairly safe and is readily metabolized if it enters the blood. However, one of the problems with dextrose is that it is readily taken up by the blood from the dialysate. Because dextrose crosses the peritoneum so rapidly, the osmotic gradient is dissipated within two to three hours of infusion. This can cause reversal of the direction of ultrafiltration, causing water to be reabsorbed from the dialysate toward the end of the time allowed for the exchange.
Another concern with respect to dextrose is that because it is taken up so rapidly by the blood, it can represent a large proportion of the patient""s energy intake. While this may not significantly effect a non-diabetic patient, it can represent a severe metabolic burden to a patient whose glucose tolerance is already impaired. Dextrose can also cause problems with respect to hyperglycemia and obesity.
Still further, a problem with dextrose is with respect ""to the preparation of a dialysis solution. Typically, dialysis solutions, similar to other medical products, are sterilized by heating. Unfortunately, heat sterilization of dextrose at physiological pH""s will cause dextrose to caramelize. To compensate for this problem, it is known to adjust the pH of the dialysate to within the range of 5 to 5.5; at this low pH dextrose will not caramelize when heated. However, it is believed that this low pH may be responsible for the pain experienced by some patients on in flow of dialysis solution and may cause other problems, e.g., may effect peritoneal host defense.
To address some of the above concerns, a number of substances have been proposed as alternatives to dextrose. However, none of the proposed materials has proven to be an adequate substitute for dextrose.
For example, dextrans, polyanions, and glucose polymers have been suggested as replacements for dextrose. Because of their high molecular weight, it is believed that their diffusion across the peritoneum and into the blood should be minimized. But, the low osmotic activity per unit mass of these materials dictates the need for larger concentrations (w/v) of these materials in the dialysis fluids in order for them to be effective. Additionally, systemic absorption of these concentrations, mainly through the lymphatics, along with slow metabolism, raises serious concern about the long term safety of these agents.
Small molecular weight substances, have also been explored. These substances include glycerol, sorbitol, xylitol, and fructose. However, these. substances are believed to raise a number of safety concerns while offering no substantial advantages over dextrose.
Amino acids appear to be an attractive substitute for dextrose in peritoneal dialysis solution. Short term studies have indicated that they are well tolerated. However, because of their low molecular weights, they are transported quite rapidly through the peritoneum, resulting in rapid loss of the osmotic gradient. In addition, rapid uptake of amino acids leads to a considerable nitrogen burden and limits the use of amino acids to one to two exchanges per day.
Recently, polypeptides have been explored as a potential class of osmotic agents. It is believed that polypeptides will have a slow transport across the peritoneum, and therefore, maintain a prolonged osmotic gradient between dialysate and blood.
U.S. Pat. No. 4,906,616 to Gilchrist et al and European Patent No. 0218900 to Klein set forth polypeptides as the osmotic agent in a peritoneal dialysis, solution. Each of these patents discusses the substitution of. polypeptides for dextrose; polypeptides are the only osmotic agent utilized in the formulations disclosed.
In Gilchrist et al, the bulk of the polypeptides have a molecular weight of 1100 or greater. Indeed, approximately 50% of the peptides have in excess of 18 amino acid residues. The polypeptides are the only osmotic agent used.(see, e.g., col. 4, lines 33-35).
In Klein, the polypeptides are a mixture of relatively low molecular weight, including an alleged substantial portion between 300 to 2,000 daltons, peptides derived from the enzymatic hydrolysis of a high quality protein. The polypeptides are the only osmotic agents used. Further, as long as the mixture of polypeptide falls within an equivalent weight of 150 to 1,500 and the molecular weight of the polypeptides is between 300 to 2,000 daltons, the polypeptide mixture is sufficient for the needs of Klein.
As set forth in detail in the examples hereinafter in this application, the polypeptide solutions proposed by Klein and Gilchrist et al have very limited clinical utility. Although larger in size, like amino acids, these polypeptide compositions are absorbed from the peritoneum quite rapidly. This leads to uremic symptoms. In addition, these materials contain polypeptides that have the potential of producing allergic reactions. This is due to the size of the polypeptides that are used.
There is therefore a need for an improved peritoneal dialysis solution.
The present invention provides an improved dialysis solution. The improved dialysis solution provides for the use of specific polypeptides as an osmotic agent with an additional osmotic agent such as dextrose.
To this end, the present invention provides, in an embodiment, a peritoneal dialysis solution comprising as osmotic agents approximately 0.25 to about 4.0% (w/v) polypeptides and approximately 0.5% to about 4.0% (w/v) dextrose.
In an embodiment, the peritoneal dialysis solution includes: approximately 120.00 to about 150.00 (mEq/L) of sodium; approximately 80.0 to about 110.00 (mEq/L) of chloride; 0 to about 45.00 (mEq/L) of lactate; 0 to about 45.00 (mEq/L) of bicarbonate; 0 to about 4.00 (mEq/L) of calcium; and 0 to about 4.00 (mEq/L) of magnesium. Preferably, the pH of the solution is approximately 6.0 to about 7.4.
In an embodiment, the polypeptides are synthetic peptides.
In an embodiment, the present invention provides a peritoneal dialysis solution comprising a polypeptide mixture as an osmotically active agent in an osmotically effective amount. The polypeptide mixture consists of not more than approximately 0.10% of polypeptides having a molecular weight of greater than 1200, not more than approximately 25% of polypeptides having a molecular weight of less than 400, and the weight average of the polypeptide mixture being within the range of approximately 400 to about 900 daltons.
In an embodiment, the peritoneal dialysis solution provides: less than approximately 5 ppm of total heavy metals; and less than approximately 500 ppb aluminum. Additionally, the peptides should have: less than approximately 50 mg/gm sodium; less than approximately 10 mg/gm chloride; less than approximately 0.2 mg/gm potassium; less than approximately 1 mg/gm magnesium; less than approximately 1 mg/gm calcium; less than approximately 1 mg/gm phosphorus; and less than approximately 5 mg/gm lactose.
In an embodiment, a two part peritoneal dialysis solution designed to be mixed prior to infusion into a patient is provided. The two part solution comprises: a first part housed in a first structure including approximately 1.0% to about 8% (w/v) dextrose and a pH of approximately 4.0 to about 5.5; a second part housed in a second structure including approximately 0.5 to about 8.0% (w/v) polypeptides and a pH of approximately 6.0 to about 7.5; and including in either the first or the second structure: 0 to about 300 (mEq/L) sodium; 0.0 to about 250.00 .(mEq/L) chloride; 0.0 to about 100.0 (mEq/L) lactate; 0.0 to about 100.0 (mEq/L) bicarbonate; 0.0 to about 10.0 (mEq/L) calcium; and 0.0 to about 10.0 (mEq/L) magnesium.
The present invention also provides for the use of polypeptides that have an amino acid composition that provides a nutritionally effective solution.
In an embodiment, the present invention also provides a solution for delivering drugs to the peritoneum.
An advantage of the present invention is that it provides an improved peritoneal dialysis solution.
Still further, an advantage of the present invention is that it provides an improved osmotic agent for use in a peritoneal dialysis solution.
A further advantage of the present invention is that it provides for the use of synthetic polypeptides for making an improved peritoneal dialysis solution.
Furthermore, an advantage of the present invention is that it provides for the ability to create peritoneal dialysis solutions that are at a physiological pH to help reduce the pain of infusion.
Moreover, an advantage of the present invention is that it has reduced osmolalities along with physiologic pH to restore phagocytic function of macrophages.
Additionally, an advantage of the present invention is that it allows the use of dextrose in the solution and sterilization of same at a pH 4.0 to 5.5 to reduce the degradation products of dextrose.
Still further, an advantage of the present invention is that it provides higher weight average molecular weight of osmotic agents to improve ultrafiltration profile.
Another advantage of the present invention is that it provides balanced supplementation of polypeptides (protein source).and dextrose (energy source) through a dialysis solution to improve the nutritional status of the renal patient.
Moreover, an advantage of the present invention is that it provides for the ability to increase infusion volumes and hence small solute clearances as a result of decrease in molar concentrations of osmotic agents.
Further, an advantage of the present invention is that it provides a solution for intraperitoneal drug delivery.
Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred embodiments and from the drawings.